title: A preclinical and clinical study of lithium in low-grade neuroendocrine tumors.
abstract: BACKGROUND
  Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3β has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3β levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs.
  
  
  METHODS
  Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8-1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3β phosphorylation, and toxicity.
  
  
  RESULTS
  Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies.
  
  
  CONCLUSIONS
  Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3β at serum levels used to treat bipolar disorders.
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. sjlubner@medicine.wisc.edu
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Lubner
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Li
authors.initials: L
authors.lastname: Ning
authors.forename: Mary
authors.initials: M
authors.lastname: Ndiaye
authors.forename: Noelle K
authors.initials: NK
authors.lastname: Loconte
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Mulkerin
authors.forename: William R
authors.initials: WR
authors.lastname: Schelman
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D010766:Phosphorylation; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride